Based on the organism's capsular polysaccharide, twelve serogroups of N. meningitidis have been identified (A, B, C, H, I, K, L, 29E, W135, X, Y and Z). Group A is the pathogen most often implicated in epidemic disease in sub-Saharan Africa. Serogroups B and C are responsible for the vast majority of cases in USA and in most developed countries. Serogroups W135 and Y are responsible for the remaining cases in USA and developed countries.
A bivalent vaccine of capsular polysaccharides from serogroups A+C is available as the product Mencevax AC™, and tetravalent mixtures of the saccharides from serogroups A+C+Y+W135 are available as the products Mencevax ACWY™ and Menomune™ [1-3]. Although effective in adolescents and adults, these vaccines induces a poor immune response and short duration of protection, because unconjugated polysaccharides are T cell-independent antigens that induce a weak immune response which cannot be boosted.
To address the poor immunity of capsular saccharides, conjugate vaccines have been developed, where the saccharides are linked to carrier proteins. Conjugate vaccines against serogroup C have been approved for human use, and include Menjugate™ [4], Meningitec™ and NeisVac-C™. Mixtures of conjugates from serogroups A+C have also been tested [5,6], and mixtures of conjugates from serogroups A+C+W135+Y have been reported [7-10].
Although the mixed conjugate vaccines are similar to the mixed saccharide vaccines, there are some key differences. In particular, the inclusion of a carrier protein in the conjugate mixtures presents new risks, particularly in terms of carrier-induced epitopic suppression (or “carrier suppression”, as it is generally known) i.e. the phenomenon whereby immunisation of an animal with a carrier protein prevents that animal from later eliciting an immune response against an antigenic epitope that is presented on that carrier [11]. This issue is of particular concern where multiple conjugates with the same carrier protein are administered simultaneously [12].
Carrier suppression has been investigated for monovalent meningococcal conjugates [13], and there has been some work in relation to mixed meningococcal conjugates. For instance, reference 14 suggests that Bordetella pertussis fimbriae should be used as the carrier in order to avoid carrier suppression in multivalent conjugate vaccines, and reference 15 suggests that carrier suppression should be dealt with by using more than one type of carrier protein in the vaccine, with H. influenzae protein D and/or tetanus toxoid (Tt) being preferred.
It is an object of the invention to provide further vaccines that comprise conjugated capsular saccharides from multiple meningococcal serogroups but which avoid the risk of carrier-induced epitopic suppression.